CN109153181B

CN109153181B - Dispensing apparatus and system for biological products

Info

Publication number: CN109153181B
Application number: CN201780030355.7A
Authority: CN
Inventors: 弗兰克·马乔里
Original assignee: Sartorius Stedim Biotech GmbH
Current assignee: Sartorius Stedim Biotech GmbH
Priority date: 2016-05-20
Filing date: 2017-05-02
Publication date: 2021-08-06
Anticipated expiration: 2037-05-02
Also published as: US20170335271A1; WO2017198448A1; US10926454B2; US10913200B2; EP3426473A1; EP3426473B1; US20170335268A1; CN109153181A

Abstract

A handheld dispensing device (10) is provided. The hand-held dispensing device comprises a first dispensing element (12) and a second dispensing element (50), wherein the first dispensing element (12) is configured to dispense a structural material and the second dispensing element (50) is configured to dispense a biological material; wherein the second dispensing element is single-use and sterilizable; and wherein the first distribution element is connectable to the second distribution element. Additionally, a dispensing system is provided. The dispensing system comprises a sterilizable chamber, at least one robotic arm assembly and dispensing apparatus, wherein the at least one robotic arm assembly and dispensing apparatus are within the sterilizable chamber, and an external control device; wherein the at least one robotic assembly is configured to move a dispensing apparatus comprising a first dispensing element and a second dispensing element, the first dispensing element being releasably connected to the second dispensing element; an external control device is connected to the at least one robotic arm assembly and configured to control the at least one robotic arm assembly; wherein the first dispensing element is configured to dispense a structural material and the second dispensing element is configured to dispense a biological material.

Description

Dispensing apparatus and system for biological products

Background

The present application relates to hand-held dispensing devices, as well as systems configured with such hand-held dispensing devices, and dispensing systems that include sterilizable chambers.

Three-dimensional (3D) bioprinting is a process that employs 3D printing techniques to generate cell patterns and living tissue from materials such as cells and supporting components, where cell function and viability are preserved within the printed construct. Recently, 3D bioprinting has begun to incorporate stent printing, i.e. providing a structure for cell support.

The leading edge solution currently used for 3D bio-printing is a large 3D printer with components that move over a printing tray filled with, for example, nutrient rich media, potentially causing particles to fall out into the tray. An example of a single use bio 3D printer is given in US2015/0035206a 1.

Alternatively, a small scale solution such as a pen printer may be utilized. For example US8834793B2 discloses a pen capable of dispensing biological material, while US9102098B2 discloses a pen capable of dispensing structural material for a printing support. Typically, structural (e.g., thermoplastic) pen printers and biomaterial pen printers (such as cell dispensers) exist separately. Electronic materials Science the ARC Center of Excellence for electronics Science developed a pen that sprayed cellular material into a biopolymer such as alginate and then wrapped the gel material with an outer layer of biopolymer. The outer and inner layers combine in the nib when squeezed.

However, the pens must be sterilized after each use and compliance with the required sterilization conditions can be cumbersome.

Therefore, there is a need for a system that allows the addition of biological materials to structural materials and scaffolds to efficiently and easily form multiple objects under sterile conditions. In particular, there is a need for a handheld device that allows a user to quickly, easily and inexpensively test multiple designs on a small scale, while checking the compatibility of structural materials and cells, and optimizing their processing, for example, prior to a biological 3D printer being scaled up to a large scale.

One application may be for laboratories and biopharmaceutical companies to rapidly screen materials, stent designs and shapes to test their cells for material compatibility with bioactive materials and to optimize their processing before scaling up. A major application for the biopharmaceutical industry may be for screening 3D printed cell products for efficacy and toxicity testing prior to use of a single-use biological 3D printer. In addition, this small scale laboratory technique can be applied to screening customers for bioactive materials, for In Vitro Diagnostic (IVD) testing on diagnostic films such as the UniSart series of products, printing on biosensors, and a variety of custom medical devices.

Disclosure of Invention

According to one aspect, a handheld dispensing device is provided. The hand-held dispensing device comprises the following parts:

a first dispensing element configured to dispense a structural material; and

a second dispensing element configured to dispense biological material;

wherein the second dispensing element is single-use and sterilizable; and

wherein the first dispensing element is releasably connected to the second dispensing element.

According to another aspect, a system is provided. The system comprises the following parts:

a hand-held dispensing device according to the first aspect;

at least one single-use bioreactor; and

at least one sterile connection assembly configured to connect the at least one single-use bioreactor to a handheld dispensing apparatus.

According to yet another aspect, a dispensing system is provided. The system comprises the following parts:

a sterilizable chamber;

at least one robotic arm assembly and a dispensing device within the sterilizable chamber, wherein the at least one robotic assembly is configured to move the dispensing device, the dispensing device comprising a first dispensing element and a second dispensing element, the first dispensing element being releasably connected to the second dispensing element; and

an external control device connected to the at least one robotic arm assembly and configured to control the at least one robotic arm assembly;

wherein the first dispensing element is configured to dispense a structural material and the second dispensing element is configured to dispense a biological material.

Drawings

Hereinafter, exemplary embodiments are described in detail with reference to the exemplary drawings. Other features will be apparent from the description and drawings, and from the claims.

Fig. 1 shows an example of a handheld dispensing device including an attachment mechanism.

Fig. 2 shows an example of a hand-held dispensing device comprising a body provided with at least one sleeve.

Fig. 3 shows other examples of handheld dispensing devices that include an attachment mechanism.

FIG. 4 shows an example of a hand-held dispensing device that includes one or more temperature regulating elements.

Figure 5 shows an example of a dispensing element comprising different mechanisms.

Fig. 6 shows an example of a system including a handheld dispensing apparatus and a source of biological material.

Fig. 7 shows an example of a system comprising a handheld dispensing apparatus and two sources of biological material.

Fig. 8 shows an example of a system including a handheld dispensing apparatus, a source of biological material, a centrifuge assembly, and a lateral flow assembly.

FIG. 9 shows an example of an external monitoring arrangement for monitoring a handheld dispensing device.

Fig. 10 shows an example of a dispensing system comprising a sterilizable chamber, a dispensing device and a manually operated external control device.

Figure 11 shows an example of a dispensing system comprising a sterilizable chamber, a dispensing device and an automatically operated external control device.

Detailed Description

Hereinafter, a detailed description of examples will be given with reference to the accompanying drawings. It should be understood that various modifications may be made to the examples. In particular, one or more elements of one example may be combined and used in other examples to form new examples. In the following, reference numerals with an apostrophe indicate the same components as corresponding common numerals but in a different configuration. For example, 10 denotes a dispensing device in a disconnected state, and 10' denotes a dispensing device in a connected state.

Fig. 1-11 illustrate different examples of dispensing devices that may provide structural and biological materials for additive manufacturing. In other words, the material extruded by the dispensing apparatus may be used to print the 3D object, i.e., to generate the 3D object. A 3D object refers to any object that exists in three-dimensional space regardless of the length, width, and depth measurements and the ratio of the length, width, and depth of the object.

Structural materials include materials that are primarily used to carry loads and/or maintain juxtaposition of component parts of the system. Structural materials are subjected to loads or stresses, wherein the stresses may be caused by mechanical, thermal, or both. The structural material may be used to construct a scaffold, i.e., a structure that provides support for other materials and cells derived from a biological system. The architecture of the scaffold is important for situations such as structure, nutrient transport and cell matrix interactions. Examples of structural materials are heated thermoplastics, hydrogels, cellulose, collagen fibers, bio-paper (and other decomposable materials), sugars, epoxies, and synthetic polymers.

Biological materials may include materials having biological systems, such as cells, cellular components, cellular products, other molecules, and materials derived from biological systems, such as proteins, antibodies, and growth factors. In addition, the dispensing apparatus may dispense other materials related to the biological material, such as, for example, supporting fluids such as nutrient rich media and metered drug products.

The dispensing apparatus described herein provides a platform for dispensing structural material, as well as biomaterial, wherein the structural material is dispensed to form a scaffold or three-dimensional printed object upon which the biomaterial can be dispensed to form a printed product. A variety of structures such as cellular structures, biological products, grafts, scaffold structures, diagnostic equipment, etc. may be printed.

The dispensing apparatus may employ a number of different techniques of additive manufacturing to build material layer by layer to form a 3D product. The dispensing devices may include, but are not limited to, extrusion printheads that deposit solid, fluid, or semi-solid materials in a continuous stream or in droplets, heated extrusion printheads that heat solid materials to help the solid materials flow as a fluid and once printed on a platform, the solid materials may solidify on the platform, and jet deposition printheads that eject micronized droplets of material on specific areas within a pattern.

The dispensing apparatus may be a hand-held apparatus held directly by an operator, as shown in fig. 1 to 9, or may be controlled by a robotic control tool, as shown in fig. 10 and 11. According to one example, the robotic control tool may be manually controlled by an operator via analog communication with a stylus manipulated by the operator. According to another example, the robotic control tool may run preprogrammed operations for printing.

The dispensing apparatus may comprise at least two dispensing elements, a first dispensing element configured to dispense the structural material and a second dispensing element configured to dispense the biological material. In some examples, the dispensing apparatus may comprise further dispensing elements, for example for dispensing material related to the biological material, for example material required to preserve the biological material and/or viability of the biological material, such as a supportive fluid. Additional dispensing elements may include, but are not limited to, pipette dispensing elements, fluid dispensing elements, spray coating dispensing elements, metered dose dispensers, nutrient rich media dispensers, gel dispensers, sputter coating dispensers, and adhesive dispensing means. The one or more dispensing elements may include a hydraulic, pneumatic, magnetic, electrical, and/or manual actuation mechanism configured to control the movement of the material until the material is dispensed from the dispensing tip. In one example, the drive mechanism may include at least one feed motor.

Additionally or alternatively, the dispensing apparatus may comprise one or more modification tools for modifying the printed object. Modifying tools may include, but are not limited to, punching tools, blades, cutting tools, rotating screws, grinding tools, inscription tools, stamping tools, and laser cutting tools.

For example, the dispensing apparatus may include a material selector switch to select which of a plurality of dispensing elements within the dispensing apparatus should dispense its material. In other words, the material selector switch may select the material to be dispensed by the dispensing apparatus.

The first dispensing element (also referred to as "structural material dispensing element") and the second dispensing element (also referred to as "biomaterial dispensing element") may be fixedly or releasably attached to each other. Likewise, further dispensing elements and/or modification tools may be connected. The dispensing elements may be directly connected, e.g. physically in contact with each other, or indirectly connected, e.g. via a third element. The connection between the dispensing elements may allow for electrical, data (e.g., sensor data, input data), and/or fluid connections between the dispensing elements.

In some examples, the dispensing elements are permanently connected to each other, wherein the dispensing device is formed as a single piece. In other examples, the dispensing elements may be releasably connectable. In other words, the dispensing element can exist in a physically disconnected state or in a connected state and can be switched back and forth from one state to another. The releasable connection may be achieved via an attachment mechanism, such as a snap mechanism, which comprises a protrusion and a corresponding mating hole for receiving the protrusion. Other attachment mechanisms may include, but are not limited to, replaceable locking tabs and mating receiving retainers, fasteners, and magnets.

In some examples, the dispensing apparatus may include an obstruction between the dispensing elements to prevent unwanted effects from being caused by the proximity of the dispensing elements when connected. For example, the first dispensing element may include a heating element to heat the structural material, and a barrier (e.g., a thermal barrier) may protect the biological material to prevent heating from negatively affecting the biological material in the second dispensing element.

At least the second dispensing element is a sterilizable, single-use element to prevent cross-contamination from one batch of biological material to another. Single-use elements are disposable elements, i.e. elements that are discarded after use. The single-use element is configured for a single use and, after a single use thereof, performs its function and is disposable. The single-use element is formed from a sterilizable material and helps to reduce the risk of contamination because it is disposable.

Prior to use, the sterilizable, single-use biomaterial dispensing element may be pre-sterilized by delivery, such as by gamma irradiation, or sterilized by an operator using a validated sterilization method, such as by autoclaving. Sterilizable, single-use biomaterial dispensing elements can be connected through standardized sterile connectors with the current infrastructure of multi-use and single-use bioreactors, microbial reactors, filters, and other biological processing equipment. For example, the biomaterial dispensing element may be connected to a biomaterial feed source, such as a bioreactor vessel, using a sterile connection. The biological material from the feed source may undergo processing such as filtration, concentration, etc. prior to being dispensed from the dispensing element.

According to one example, a sterilizable, single-use biomaterial dispensing element can be coupled to a multi-use structural material dispensing element. According to another example, the entire dispensing apparatus including the first and second dispensing elements may be sterilizable and single-use.

The dispensing apparatus is intended to allow an operator to quickly screen for structural materials that are compatible with biological materials. The operator can easily create a plurality of shapes, designs, structures, holders and printing programs to optimize to an optimal combination. In essence, this is a determination of whether the printed material type and shape is compatible with maintaining or promoting cell growth and optimizing such growth prior to scaling up operations on a large scale biological 3D printer, such as a single use printer assembly.

The dispensing device may include one or more orientation and position sensors or may be tracked positionally by an external monitoring device to record movement, material dispensing, and status. A qualified print design may be copied from a small scale dispensing device within a large scale biometric 3D printer using this stored positional file of recorded movement of the dispensing device. In other words, the stored information about the method and circumstances of dispensing can be used to print structural and biological materials using a 3D printer in exactly the same way that an operator uses a dispensing apparatus to construct a three-dimensional object.

Fig. 1 shows an example of a handheld dispensing device 10 that includes an attachment mechanism. The sterilizable, single-use second dispensing element 50 is directly connected to the multi-use first dispensing element 12 using an attachment mechanism. View 'a' is a side view of the dispensing apparatus 10 in a disconnected state, wherein the dispensing apparatus 10 comprises a first dispensing element 12 and a second dispensing element 50 disconnected from each other.

The first dispensing element 12 of the dispensing apparatus 10 may include a printer body 14 having a plurality of components mounted therein. The multi-use first dispensing element 12 of the dispensing apparatus 10 may use a structural material 16 that is, for example, a thermoplastic material such as polylactic acid (PLA), Acrylonitrile Butadiene Styrene (ABS), carbon fiber, a low melting point metal, and/or other low melting point structural materials. In other examples, the structural materials may include, but are not limited to: hydroxyapatite (HA), collagen, fibrin, hydrogels, chitosan, hyaluronic acid, sugars, gels and powders.

In this example, a length of structural thermoplastic material 16 may be inserted into the top of the multiple use first dispensing element 12 and the dispensing speed is determined by a feed motor 18, wherein the feed motor 18 has at least one gear 20 to control the movement of the structural thermoplastic material 16. Multiple feed motors 18 and gears 20 may be utilized to ensure a steady flow of the structural material 16 through the top of the first dispensing element 12 until the structural material 16 is dispensed from the dispensing tip 38 to prevent jamming inside the apparatus.

Structural material 16 may be moved through inner tubular member 22 to heating element 24, such as an electrically powered heating element, heating element 24 being powered by electrical connection 46. In this example, the heating of the thermoplastic structural material 16 and the dispensing through the narrow dispensing tip 38 may constitute an ultra-high temperature sterilization that destroys microorganisms within the structural material 16 even if the structural material 16 is from a non-sterile supply. Other dispensing methods without heating or compression may require sterile connection to a sterile feed prior to use.

An operator may control the temperature of the heating element 24 and the dispensing of the structural material 16 through a computer control panel 26, wherein the computer control panel 26 may include a processing device 28, a memory storage device 30, and a wireless communication device 32. The multiple use first dispensing element 12 may include one or more control devices to allow an operator to control the flow of material, for example, using the dispense and retract buttons 34. Additionally, a material selector switch 36 may be provided to select the material that should be dispensed by the dispensing apparatus 10 from a variety of materials, such as to switch from dispensing the structural material 16 to dispensing the biological material once the second dispensing element 50 is connected to the first dispensing element 12. Additionally or alternatively, a remote input device (not shown), such as a wired or wireless foot pedal, wearable device, or other remote input, may be utilized to control the flow of material and select the material to be dispensed.

The dispensing apparatus 10 may include a plurality of positioning sensors 44 in the first dispensing element 12, the plurality of positioning sensors 44 including, but not limited to: motion sensors, orientation sensors, gyroscopic sensors, environmental sensors, cameras, microscopic cameras, thermal cameras, depth sensors, ultrasonic devices, magnetometers, accelerometers, proximity sensors, Global Positioning System (GPS) devices, Internal Measurement Units (IMUs), and internal or external positioning sensors. Information from the orientation and positioning of the dispensing apparatus 10 used by the operator may be saved in a file with which copies of the structural and biological material may be printed in exactly the same way as manually printed using a large scale single use biological 3D printer device (not shown). Additionally or alternatively, the sensors used for positioning may also be used to scan the workspace, print tray, and/or three-dimensional object before printing, during printing, and/or after printing. These scans can be used to determine the structure or microstructure of the printed material.

The multi-use first dispensing element 12 of the dispensing apparatus 10 may use an attachment mechanism 42, such as a snap-fit mechanism, to attach to a corresponding attachment mechanism 64 on the single-use second dispensing element 50. In this example, the first distribution element 12 and the second distribution element 50 are directly connected. The attachment mechanism 42 may connect the single-use second dispensing element 50 in communication with the multiple-use first dispensing element 12, wherein the connection may establish electrical, mechanical, and/or fluid communication. In this example, the connection between the multi-use first dispensing element 12 and the single-use second dispensing element 50 may include a thermal barrier 40 to prevent residual heat from the heating element 24 from negatively affecting the dispensing of the biological material.

The single-use second dispensing element 50 may be constructed from a sterilizable material and may be sterilized using proven methods such as gamma irradiation, autoclaving, and/or chemical sterilization. For example, the single-use second dispensing element 50 may include a printer body 52 that houses multiple components. Additionally, the single-use second dispensing element 50 may include at least one physical sterile connector and a tube member 58, wherein the at least one physical sterile connector may include, for example

Two or more parts of a connector, the

The connector has a tube that connects to an external sterile feeding source of cells, media and/or other biological material, with tube member 58 delivering sterile feeding material from the sterile connection to inner tube 54. Alternatively, the sterile connection may be made with at least one heat-weldable tube, which may be used

Can be welded by heatTo be connected with a tube sealer (not shown).

The inner tube 54 extends the length of the printer body 52 to a dispensing tip portion 56 at the end opposite the tube member 58. The dispensing tip 56 may include a variety of shapes to alter the dispensing profile of the dispensed material, such as slow and focused or sprayed on a defined area or pattern. Additionally, the dispensing tip portion 56 may also include a restriction device (not shown) that may be partially closed to restrict the flow of material through the tip portion 56, or completely closed to prevent the entire flow of material through the tip portion 56. Alternatively, the operator may select between multiple dispensing tip portions having different geometries for different dispensing patterns, either by moving a carousel pulley comprising multiple tip portion configurations (not shown) on the printer body 52, or by attaching a pre-sterilized tip portion (not shown) to the dispensing tip portion 56.

When the inner tube 54 is filled with material, the inner tube 54 may be properly vented using a vent filter 62, such as a fully testable, sterilization grade vent filter. The movement of the material through the single-use second dispensing element 50 may be provided by an external source such as a pneumatic pressure source, a pump, or an electric motor. Alternatively, the pump, electric motor and/or pneumatic pressure source may be located inside the dispensing apparatus 10.

View ' B ' is a side view of the dispensing apparatus 10 ' in the connected state. In this example, the multiple use first dispensing element 12 ' is connected using the attachment mechanism 42 ', the attachment mechanism 42 ' being attached to a corresponding attachment mechanism 64 ' on the single use second dispensing element 50 '. The material selector switch 36 ' is movable from a position for selecting the multi-use first dispensing element 12 ' to a position for selecting the single-use second dispensing element 50 ', whereby the material dispensing and retraction buttons may be utilized by an operator to dispense the biomaterial and/or material related to the biomaterial. The dispensing apparatus 10 ' in the connected state may comprise an ergonomic molded handle on or through the first dispensing member 12 ', the single-use second dispensing member 50 ', for comfortable use of the apparatus by an operator.

An electrical power cable 48 may be inserted into the electrical connector 46 to power the electrical heating element 24, the at least one feed motor 18, or other electrical components. Alternatively, the dispensing apparatus 10 may be powered by at least one of an exemplary rechargeable battery, an ac wired connection, a drive communication port, a solar unit, a mechanical power source, an electromechanical power source such as a hand crank, or a wireless power source.

The single-use second dispensing element 50 'may be connected to the bio-feed source 66 via at least one sterile connection 60'. Sterile connector 60' may be used, for example

Sterile connector manufacture of connectors and/or other physical sterile connectors, and/or may be accomplished by heat welding a length of heat-weldable tubing to a feeding assembly for sterile connection with biological feed source 66.

Fig. 2 shows an example of a hand-held dispensing device 100 comprising a body provided with at least one sleeve 120.

View 'a' is a side view of the handheld dispensing apparatus 100 in a disconnected state. The dispensing apparatus 100 comprises a reusable multi-use first dispensing element 102 and a sleeve 120 for insertion of a sterilizable single-use second dispensing element 122. The multi-use first dispensing element 102 of the dispensing apparatus 100 may include a printer body 104 with a plurality of components mounted therein. In one example, the sleeve 120 may be part of the printer body 104 such that the sleeve 120 and the second dispensing element 122 are directly connected.

Multiple uses of the first distribution member 102 may utilize a structural material 106 such as a thermoplastic material. In other examples, the structural material may include any of Hydroxyapatite (HA), collagen, fibrin, hydrogel, chitosan, hyaluronic acid, sugar, gel, and powder.

In this example, a length of thermoplastic structural material 106 may be inserted into the top of the multiple use first dispensing element 102 and the dispensing speed may be determined by a feed motor having one or more gears to control the movement of the thermoplastic structural material 106. The structural material 106 can be moved through the inner tubular member toward a heating element 108 that can heat the structural thermoplastic material 106 and dispense the structural thermoplastic material 106 through a narrow dispensing tip portion 112.

The operator may control the temperature of the heating element 108 and the dispensing of the structural material 106 through a computer control board 114, wherein the computer control board 114 may include processing devices, memory storage devices, and wireless communication devices. The multiple use first dispensing element 102 may include one or more control devices to allow an operator to control the flow of material, for example, using the dispense and retract button 110 and the material selector switch 116, wherein the material selector switch 116 selects material from the multiple dispense material. Illustratively, once the single-use second dispensing element 122 is connected to the first dispensing element 102, the material selector switch may switch from dispensing the structural material 106 to dispensing the biological material.

The dispensing apparatus 100 may include a plurality of positioning sensors 118, the plurality of positioning sensors 118 including, but not limited to: motion sensors, orientation sensors, gyroscopic sensors, environmental sensors, cameras, depth sensors, magnetometers, accelerometers, proximity sensors, GPS devices, and internal or external positioning sensors.

The printer body 104 of the multi-use first dispensing element 102 may include a barrel or sleeve 120 into which a single-use second dispensing element 122 may be inserted. The connection between the first and

second dispensing elements

102, 122 via the insertion barrel 120 may also be facilitated by an attachment mechanism, such as a snap-fit mechanism. In this example, the first distribution element 102 and the second distribution element 122 are directly connected. Insertion and optional attachment of the single-use second dispensing element 122 to an attachment mechanism may place the second dispensing element 122 in communicative contact with the multi-use first dispensing element 102. The connection may establish electrical, mechanical and/or fluid communication. In this example, the connection between the multi-use first dispensing element 102 and the single-use second dispensing element 122 may include a thermal barrier to prevent residual heat from the heating element 108 from negatively affecting the dispensing of the biological material.

The single-use second dispensing element 122 may be constructed from a sterilizable material and may be sterilized using proven methods such as gamma irradiation, autoclaving, and/or chemical sterilization. For example, the single-use second dispensing element 122 may include a printer body with a plurality of components mounted therein. Additionally, the second distribution element 122 may include a second distribution element such as

At least one physical sterile connector 124 of connectors, the physical sterile connector 124 comprising two or more components, the physical sterile connector 124 having a tube component 126 connected to an external sterile feeding source of cells, media and/or other biological material, wherein the tube component 126 can transport the sterile feeding material from the sterile connector to the inner tube 128. Alternatively, the aseptic connection may be made with at least one heat-weldable pipe, which may be used

A heat weldable tube sealer (not shown) makes the connection.

The inner tube 128 may extend the length of the printer body up to a dispensing tip 132, the dispensing tip 132 being at an end opposite the end connected to the tube member 126. The dispensing tip 132 may include a number of shapes to alter the dispensing profile of the dispensed material, such as slow and focused or sprayed on a defined area or pattern. When the inner tube 128 is filled with material, the inner tube 128 may be suitably vented using a vent filter 134, such as a full testable, sterilization grade vent filter.

The movement of the material through the single-use second dispensing element 122 may be provided by an external source, such as a pneumatic pressure source, a pump, or an electric motor. Alternatively, the pump, electric motor and/or pneumatic pressure source may be internal to the dispensing apparatus 100.

View ' B ' is a side view of the dispensing device 100 ' in the connected state. In this example, the single-use second dispensing element 122' may be inserted into the sleeve 120 and also connected using an attachment mechanism. The material selector switch 116 ' is movable from a position for selecting a multiple use first dispensing element 102' to a position for selecting a single use second dispensing element 122 ', whereby the biomaterial and/or biomaterial-related material may be dispensed by an operator using the material dispensing and retraction button 110. The dispensing apparatus 100 'in the connected state may include a molded handle on the first dispensing element 102' that is ergonomic for the operator to comfortably use the apparatus.

The single-use second dispensing element 122 'may be connected to the bio-feed source 130 via at least one sterile connection 124'. Sterile connection 124' may be achieved by heat welding a length of heat-weldable tubing to a feeding assembly for sterile connection to a biological feeding source. The sterile connection 124' may be used, for example

Sterile connector manufacture of connectors and/or other physical sterile connectors, and/or may be accomplished by heat welding a length of heat weldable tubing to a feeding assembly for sterile connection to a biological feeding source.

The dispensing apparatus 100' may be powered by a power cable (not shown), an exemplary rechargeable battery, a drive communication port, a solar unit, a mechanical power source, an electromechanical power source such as a hand crank, or a wireless power source.

View 'C' is a side view of the dispensing apparatus 150 in a disconnected state. The first and

second distribution elements

162, 164 may be similar to the corresponding elements described with reference to views 'a' and 'B'. However, the body of the first dispensing element 162 does not include a sleeve. Instead, in this example, there is a central connecting body 152 that includes a plurality of barrels or

sleeves

154 and 156, wherein a plurality of first and

second distribution elements

162 and 164 may be inserted into the barrels or

sleeves

154 and 156 to form a completed assembly. Thus, the first and

second distribution elements

162, 164 may be indirectly connected via the central connecting body 152.

An attachment mechanism may also be used to secure the dispensing element in the

sleeves

154 and 156. The attachment mechanism may connect the plurality of first and

second distribution elements

162, 164 in communication with the central connecting body 152, wherein the connection may include electrical, mechanical, and/or fluid communication.

In this example, central connecting body 152 may be sterilizable and single use. Additionally, the plurality of first and

second distribution elements

162, 164 connected to the central connecting body 152 may be sterilizable and single-use. The central connecting body 152 may include a thermal barrier 158 between the plurality of barrels 154 and the barrel 156 to prevent thermal energy transfer to avoid negatively affecting the second distribution element 164. Additionally, the central connecting body 152 may include a plurality of control elements 160 such as buttons, switches, knobs, and other operator control elements similar to those described with reference to view 'a' and view 'B'.

View 'D' is a side view of the dispensing apparatus 150 'where both the multi-use first dispensing element 162' and the single-use second dispensing element 164 separated by the thermal barrier 158 are in a connected state and attached to the central connecting body 152 using an attachment mechanism. Central connecting body 152 may include an ergonomically molded handle for comfortable use of the device by an operator.

In this example, the multiple use first dispensing element 162' may comprise a computer control board including a processing device, a memory storage device, and a wireless communication device. A plurality of control elements 160 on the central connecting body 152 may be arranged and communicatively attached to a computer control panel element to receive inputs from the control elements 160. Alternatively, the computer control board and other devices may be partially or entirely integrated into the central connecting body 152.

The single-use second dispensing element 164 'may be connected to a biological feed source, such as a material originating from or processed from a multi-use bioreactor or a single-use bioreactor, via at least one sterile connection 166'. For example, the aseptic connection is constituted by an aseptic connector,the aseptic connector is such as

Connectors and/or other physical sterile connectors where two or more components 166' and 168 are connected together. In other examples, multiple uses of first dispensing element 102 may require a sterile connection for some structural materials such as hydrogel, Hydroxyapatite (HA), collagen, fibrin, chitosan, hyaluronic acid, etc., which cannot be heated to extreme temperatures. Because heating ensures that all microorganisms in the structural material are killed prior to dispensing, if not heated, the feed material may need to be sterilized prior to connection to the dispensing apparatus 150 to prevent any potential contamination of the final printed object.

As shown in fig. 1 and 2, the structural material distribution element may generally include at least one feed motor that controls movement of the structural material, at least one innerduct that contains the structural material, and at least one distribution tip that distributes the structural material. In addition, the structural material dispensing element may include at least one control device (e.g., a dispense and retract button and/or a material selector switch) to control the flow of material and to select the material that must be dispensed when other dispensing elements are connected to the structural material dispensing element. Additionally or alternatively, the structural material dispensing element may include a processing device, such as a computer control board, to control the dispensing process. Illustratively, the structural material dispensing element may comprise a heating element to heat and melt the structural material, and the processing device may be configured to control the temperature of the heating element.

In general, the biomaterial dispensing element may comprise a body formed of a sterilizable material, at least one inner tube containing the biomaterial, at least one venting filter that properly vents the inner tube when the venting filter is filled with the material, and at least one dispensing tip that dispenses the biomaterial. In addition, the biomaterial dispensing element may include an aseptic connector that connects to a material feed source for aseptic transfer and dispensing of the biomaterial.

The combination of a biomaterial dispensing element and a structural material dispensing element as shown in fig. 1 and 2 is but one of many possible configurations of handheld dispensing devices. Fig. 3 shows further examples of handheld dispensing devices comprising an attachment mechanism, wherein a plurality of dispensing elements may be connected and/or external obstacles may be provided between the connected dispensing elements.

View 'a' is a side view of a dispensing apparatus 230 with a plurality of connectable dispensing elements in a disconnected state. In this example, the dispensing elements making up the dispensing apparatus 230 may include a multi-use first dispensing element 232, a single-use second dispensing element 262, and a pipette liquid dispensing element 244, which may be multi-use or single-use. In other examples, portions of dispensing device 230 may be different dispensing elements, wherein the dispensing elements may include, but are not limited to: a spray dispenser, a metered dose dispenser, a liquid medium dispenser, a gel dispenser or a sputter coating dispenser. In addition, other modifying tools that modify dispensing structural materials and/or biological materials, such as perforating tools, blades, rotating screws, laser cutters, pressurized sterile air, membrane dispensers (for dispensing membranes, vests, films, and shape memory polymers), electrospun fiber/nanofiber dispensers, dispensers for fluorescent or DNA identification labels, or other tools, may be attached to dispensing apparatus 230 for modifying printed objects. The use of these post-printed modification tools for surface modification and the generation of internal paths within the printed three-dimensional structure are described in U.S. patent application 14/680180, which is incorporated herein by reference.

In this example, the structural material 234, which may illustratively be a thermoplastic material, is dispensed multiple times using the first dispensing element 232. Structural material 234 can be moved through an inner tubular member (not shown) to a heating element (not shown) and dispensed through a narrow dispensing tip portion 240. An operator may control the dispensing temperature of the structural material 234. In addition, the operator may control the flow of material 234 through a plurality of control devices such as a material dispensing and retraction button 238 and a material selector switch 236, wherein the material selector switch 236 selects from a plurality of materials the material that should be dispensed by the dispensing device 230 when the second dispensing element 262 is connected with the pipette liquid dispensing element 244.

Multiple use first dispensing element 232 may use an attachment mechanism 242, such as a snap-fit mechanism, to attach to a corresponding attachment mechanism 258 on pipette liquid dispensing element 244.

Pipette liquid dispensing element 244 may include plunger button 246, volume adjustment knob 250, volume indicator display 252, tip ejector button 248, tip retainer 254, and disposable pipette tip 256. The pipette liquid dispensing element 244 may include an internal piston assembly (not shown) having a barrel, shaft, spring, and O-ring. The pipette liquid dispensing element 244 may be used to dispense metered volumes of a pharmaceutical or chemical product, or to dispense a liquid medium or other growth promoting fluid to a printed object.

The pipette liquid dispensing element 244 may use an attachment mechanism 260, such as a snap-fit mechanism, to attach to a corresponding attachment mechanism 270 on the single-use second dispensing element 262.

Single-use second dispensing element 262 may be constructed of a sterilizable material and may be sterilized using proven methods such as gamma irradiation, autoclaving, and/or chemical sterilization. In this example, single-use second dispensing element 262 may include a printer body with a plurality of components mounted therein. In addition, single-use second dispensing element 262 may include at least one physical sterile connector and tube component, such as

At least one physical sterile connector of the connector includes two or more components having a tube connected to a sterile feeding source external to the cells, media and/or other biological material, the tube components transporting the sterile feeding material from the sterile connector to an inner tube (not shown).

An inner tube (not shown) may extend the length of the printer body up to the dispensing tip 268 at one end. The dispensing tip 268 may include a number of shapes to alter the dispensing profile of the dispensed material, such as slow and focused or sprayed on a defined area or pattern. When the inner tube is filled with material, a vent filter 266, such as a full testable, sterilization grade vent filter, may be used to properly vent the inner tube (not shown). Movement of the material through the single-use second dispensing element 262 may be provided by an external source, such as a pneumatic pressure source, a pump, or an electric motor. Alternatively, the pump, electric motor, and/or pneumatic pressure source may be internal to the dispensing apparatus 230.

View 'B' is a side view of the dispensing apparatus 230 with a plurality of connectable dispensing elements in a connected state. In this example, multi-use first dispensing element 232 ', pipette liquid dispensing element 244 ', and single-use second dispensing element 262 ' are connected with their respective attachment mechanisms. The attachment mechanism may bring pipette liquid dispensing element 244 ', single-use second dispensing element 262 ', and multi-use first dispensing element 232 ' into communicative contact with one another, wherein the connection may establish electrical, mechanical, and/or fluid communication. Between each of the plurality of dispensing elements within dispensing device 230', there may be a thermal barrier (not shown) to prevent thermal energy transfer from adversely affecting pipette liquid dispensing element 244 and second dispensing element 262. The dispensing device 230 'in the connected state may comprise an ergonomic molded handle on the first dispensing element 232', the pipette liquid dispensing element 244 ', the single use second dispensing element 262', or across all elements for comfortable use of the device by an operator.

In the connected configuration of dispensing device 230 ', material selector switch 236' may change the selected dispensing element to, for example, pipette liquid dispensing element 244 'or single use second dispensing element 262' to allow an operator to control the flow of material using material dispense and retract button 238. Pipette liquid dispensing element 244' may utilize either material dispensing and retraction button 238 or pipette plunger button 246 on the dispensing element itself, depending on which is more comfortable for the operator to operate. The dispensing

tip portions

240, 254, and 268 of the respective dispensing elements are sufficiently spaced apart to prevent overlap with or jetting to another element, such as to prevent jetted coating liquid from the pipette liquid dispensing element 244 'from contacting the heated dispensing tip portions of the first dispensing element 232'.

Single-use second dispensing element 262 'may be connected to bio-feed source 272 via at least one sterile connection 264'. Sterile connector 264' may be used, for example

Sterile connectors of the connector and/or other physically sterile connectors, and/or may be achieved by heat welding a section of heat weldable tubing to the feeding assembly for sterile connection with a biological feeding source.

View 'C' is a side view of the dispensing apparatus 280 in which the multi-use first dispensing element 282 is attached to a thermal barrier 286 to prevent the heating element as discussed in the above examples from adversely affecting the biological material within the single-use second dispensing element 284. The thermal barrier 286 may be formed such that communicative contact is provided between the multi-use first dispensing element 282 and the single-use second dispensing element 284 by an attachment mechanism (not shown). The thermal barrier 286 may extend down to the dispensing tip portion 288 and the dispensing tip portion 289 to prevent any negative thermal effects from the heating element during dispensing of the structural material from the dispensing tip portion 288 and dispensing of the biological material from the dispensing tip portion 289.

View 'D' is a side view of dispensing device 290 with multi-use first dispensing element 292 attached to isolation element 296 to prevent heating elements as discussed in the above examples from adversely affecting the biological material within single-use second dispensing element 294. Isolation member 296 can be formed such that communicative contact is provided between multi-use first dispensing member 292 and single-use second dispensing member 294 by an attachment mechanism (not shown). The isolation element 296 may extend only partially along a section of the first and

second distribution elements

292, 294 to leave a gap between the distribution tip 298 and the distribution tip 299 where the air flow from the working space may prevent any negative thermal effects from the heating element during the distribution of the structural material from the distribution tip 298 and the distribution of the biological material from the distribution tip 299.

As discussed with reference to fig. 1-3, the structural material distribution element may include a temperature adjustment element such as a heating element. Additionally or alternatively, other temperature regulating elements, such as cooling elements and warming elements, may be included in the dispensing apparatus to regulate the temperature of the material to be dispensed. In one example, temperature regulation may be accomplished by one or more lines filled with a thermal regulation fluid in the distribution apparatus. The thermal conditioning lines may be filled, suitably vented and recycled using an external pump and/or pneumatic pressurization source. The temperature regulating device for the fluid may be an external device that heats and/or cools the thermal regulating fluid within the container and recirculates the fluid through the thermal regulating line. In another example, temperature adjustment may be accomplished with a single-use chemical temperature adjustment element that may use exothermic and/or endothermic chemical reactions as a single-use temperature adjustment of the material to be dispensed. FIG. 4 shows an example of a hand-held dispensing device that includes one or more temperature regulating elements.

View 'a' is a side view of a single-use dispensing apparatus 300 including a printer body 302 with a plurality of components mounted therein, wherein the plurality of components are made of sterilizable materials and can be sterilized using proven methods such as gamma irradiation, autoclaving, and/or chemical sterilization. In this example, the dispensing apparatus 300 can include a structural material dispensing element that dispenses material from the dispensing tip 312 and a biomaterial dispensing element that dispenses material from the dispensing tip 318. In other words, the dispensing elements are permanently connected and may be formed together. The single-use dispensing apparatus 300 may include an ergonomic molded handle for comfortable use of the apparatus by an operator.

Structural material dispensing elements of the dispensing apparatus 300 may utilize structural material 304, such as a low melting thermoplastic material having a lower melting point than the melting point of the printer body 302 and other internal components within the dispensing apparatus 300. In other examples, the structural material may include Hydroxyapatite (HA), collagen, fibrin, hydrogel, chitosan, hyaluronic acid, sugar, gels, powders, or other structural materials that do not require heating above the melting temperature of the plastic material used by the printer body 302 and other internal components within the dispensing apparatus 300.

The structural material 304 may be inserted into the top of the structural material dispensing element portion of the dispensing apparatus 300 and the dispensing speed may be determined by a feed motor (not shown) having a plurality of gears (not shown) to control the movement of the thermoplastic structural material. In this example, where the entire dispensing apparatus is single use, the feed motor (not shown) may be driven by an external pneumatic/hydraulic source attached to the fluid driver and the temperature-regulating connector 306.

In one example, a pneumatic pressure source may be connected to the fluid driver and the temperature regulating connector 306. In this case, the exhaust gas may simply be vented of pressure in a direction away from the print object through filter 305 after running through a feed motor (not shown), or the filter may be connected to a section of pipe that removes excess compressed air from the working area. In another example, a hydraulic pressure source may be connected to the fluid driver and the temperature regulating connector 306. In this case, after running through the feed motor (not shown), the waste liquid pressure can use a line to discharge the compressed fluid away from the work zone, or to recover the fluid in a vessel (not shown) where it can be pressurized and recycled through the apparatus.

Structural material 304 may be moved through an inner tubular member (not shown) to a single-use heating element (not shown), which is described in more detail with reference to views 'B' and 'C'.

The single-use biomaterial dispensing element of the dispensing apparatus 300 may be connected to a biological feed source via at least one sterile connection 314. When the inner tube is filled with the material,a vent filter 316, such as a full testable, sterilization grade vent filter, may be utilized to properly vent the inner tube (not shown). Sterile connection 314 may be used, for example

Sterile connectors of the connector and/or other physically sterile connectors are made and/or may be accomplished by heat welding a section of heat weldable tubing to a feeding assembly that is aseptically connected to a biological feeding source.

An operator may control the dispensing of the structural material and the biomaterial through the dispense and retract button 310 and the material selector switch 308, wherein the material selector switch 308 may be switched from structural material dispensing to biomaterial dispensing. In this example, the control may adjust the direction and force of pneumatic/hydraulic pressure that controls the flow of material within the single-use device 300.

View 'B' is a side view of a single-use dispensing apparatus 320 that includes a fluid temperature control mechanism. The single-use dispensing device 320 may be a possible implementation of the single-use dispensing device 300.

The single-use dispensing apparatus 320 may include a printer body 322 having a plurality of components housed therein, the plurality of components being made of sterilizable materials and being sterilizable using proven methods such as gamma irradiation, autoclaving, and/or chemical sterilization.

The apparatus 320 may include internal recirculation passages within the thermal regulating assembly 333 to deliver fluids for heating and cooling elements within the dispensing apparatus 320. The individual fluid conducting elements may be connected by a single connection such as the fluid driver and temperature regulating connector 306 as shown in view 'a' to align and connect each of the individual lines. The lines may be isolated and insulated from each other to prevent residual heat or cooling from adversely affecting the temperature of nearby temperature control lines. The lines may include at least one of a fluid line 330, a heating line 340, a cooling line 346, and a warming line 366, which will be described in greater detail below.

Illustratively, first dispensing element 324 may include structural material 326, feed motor 328, breather filter 332, inner tube 334, heating element 336, cooling element 342, and dispensing tip 348. The feed motor 328 may be driven by an external pneumatic pressure source attached to the fluid line 330. After running through the feed motor 328, the exhaust gas may simply be vented of pressure in a direction away from the print object through a vent filter 332, or the vent filter 332 may be connected to a section of tubing that removes excess compressed air from the work area.

Feed motor 328 may rotate a plurality of gears that feed structural material 326 into inner tube 334 to heating element 336. Heating element 336 may include components that circulate heating fluid, such as heated sterile filtered water, ethylene glycol, and/or steam, from an external source of temperature regulated fluid through heating line 340. The heating line 340 may be connected to an inner heating recirculation loop 338, and the inner heating recirculation loop 338 may be insulated to protect internal components and other temperature controlled fluid lines from the adverse effects of elevated temperatures. The heating element 336, heating line 340, and inner heating recirculation loop 338 may be made of high melting point plastic and/or metal components to resist deformation and/or facilitate heat transfer during recirculation of the heating fluid to melt and dispense the structural material 326.

The single-use dispensing apparatus 320 may be pre-sterilized and provided without any fluid in the fluid line. The line may then be filled with a thermal conditioning fluid prior to use. The thermal conditioning lines may be filled, suitably vented and recycled using an external pump (not shown) and/or a pneumatic pressurization source (not shown). The temperature regulating device may be an external device that heats and/or cools the thermal regulating fluid within the container and recirculates the fluid through the thermal regulating line within the dispensing device 320.

In some cases, particularly if the temperature adjustment of the heating element uses a heating fluid that is not tightly controlled, the structural material 326 may be partially cooled after it passes through the heating element 336, thereby achieving a desired dispensing rate and stability of the structural material 326 before it is dispensed from the structural material dispensing tip 348. The cooling element 342 may include components to circulate cooling fluid, such as chilled, cold or frozen sterile filtered water, saline, ethylene glycol, and/or air, through the cooling line 346 from an external source of temperature regulated fluid. The cooling line 346 may be connected to the internal cooling recirculation loop 344, and the internal cooling recirculation loop 344 may be insulated to protect internal components and other temperature control fluid lines from the negative effects of the cooling temperature. The cooling element 342, the cooling line 346, and the internal cooling recirculation loop 344 may be made of plastic and/or metal components.

Temperature sensors may be embedded in the heating element 336 and the cooling element 342 to provide feedback to the computer control board and/or operator regarding the dispensing within the dispensing apparatus 320. The second dispensing element 356 may include a thermal barrier to prevent the heating element 336 and/or the cooling element 342, as well as the internal heating recirculation loop 338 and thermal fluid control lines, from adversely affecting the dispensing of the biological material.

The second dispensing element 356 can include a warming element 364 to maintain the cells and/or biological material at a stable temperature, such as an incubation temperature of 37 ℃ during dispensing. Warming element 364 may include components that circulate warming fluid, such as warming sterile filtered water, saline, ethylene glycol, and/or air, from an external source of temperature regulating fluid through warming line 366. The warming line 366 may be connected to an internal warming recirculation loop 365, which internal warming recirculation loop 365 may be insulated to protect internal components and other temperature control fluid lines from the negative effects of the warming temperature. The internal augmented temperature recirculation loop 365 may be positioned such that the line passes through the thermal obstruction 354. The warming element 364 can be positioned such that the warming element 364 provides consistent warming and heat transfer over the entire length of the inner tube 362 prior to dispensing of the biomaterial dispensing tip 368.

The second dispensing element 356 may be connected to the biological feed source via at least one sterile connection 358. When the inner tube 362 is filled with material, the inner tube 362 may be suitably vented using a vent filter 360, such as a full testable, sterilization grade vent filter. Sterile connector 358 may be used, for example

The operator may control the dispensing of the structural material and the biomaterial by dispensing and retracting the button 350 and the material selector switch 352, wherein the material selector switch 352 may switch from dispensing the structural material 326 to dispensing the biomaterial. In this example, the direction and force of the adjustable pneumatic pressure is controlled, and the pneumatic pressure controls the flow of material within the single-use device 320.

View 'C' is a side view of a single-use dispensing device 370 that includes a plurality of single-use chemical heating elements. The single-use dispensing device 370 may be a possible implementation of the single-use dispensing device 300.

The single-use dispensing device 370 may include a printer body 372 having a plurality of components mounted therein, which are made of sterilizable materials and may be sterilized using an empirical method.

The device 370 may include a single-use chemical heating element based on an exothermic oxidation mechanism such as iron when exposed to air, or a reusable chemical heating element based on a mechanism such as exothermic crystallization of a supersaturated solution.

The first dispensing element 374 of the apparatus 370 may include structural material 376, a feed motor 378, a breather filter 380, an inner tube, a dual chamber

chemical heating element

382 and 384, and a dispensing tip. The feed motor 378 may be driven by an external pneumatic pressure source attached to the fluid line 383.

After running through the feed motor 378, the exhaust gas may simply vent the pressure in a direction away from the print object through the breather filter 380, or the breather filter 380 may be connected to a section of the tube that removes the remaining compressed air from the work area.

The feed motor 378 may rotate a plurality of gears that feed the structural material 376 into the inner tube 334, to the dual chamber heating element 382 and the heating element 384. The dual chamber heating element 382 and heating element 384 may include two different chemical materials, such as calcium oxide and water, with the dual chamber heating element 382 and heating element 384 being held apart by a seal 388. Illustratively, when the seal 388 is removed by an operator by pulling a tape including the seal 388 from the socket 386 in a direction 390, the two spaced apart chemicals in the dual chamber heating element 382 and heating element 384 mix. This mixing results in an exothermic reaction that causes the heating element to increase in temperature. In other examples, a single stage chemical heating element (not shown) may be used, where the seal 388 may be removed to expose the single stage element to air, with exothermic oxidation of iron as the heating source. The chemical heating method used must be of sufficient heat and duration to provide a stable amount of thermal energy for melting the structural material 376 intended for use.

Second dispensing element 392 of apparatus 370 may include thermal barrier 404 to prevent

chemical heating elements

382 and 384 from adversely affecting the dispensing of biological material. Second dispensing element 392 may include a dual chamber warming element 396 and warming element 394, which may include two different chemical materials held apart by seal 400. Illustratively, when the sealer 400 is removed by an operator by pulling the tape including the sealer 400 from the socket 398 in direction 402, the two spaced chemicals in the dual chamber warming element 396 and the warming element 394 mix, resulting in an exothermic reaction that causes the warming element to increase in temperature. Warming element chamber 394 can use gangue and/or gels to regulate and control the exothermic reaction, thereby preventing residual heat from damaging the biological material as it moves through the inner tube. Alternatively, a supersaturated solution of sodium acetate may be exposed to the metal disk by removing seal 400, which helps initiate nucleation and crystallization of heat generated from the exothermic reaction.

Temperature sensors may be embedded in the heating and warming elements to provide feedback to the computer control board and/or operator regarding the dispensing within the dispensing apparatus 370. Multiple heating and warming element chambers may be used to maintain heating for a defined duration depending on the length of time required to complete the process of material to the printed object. Alternatively, the operator may remove the chemical heating elements used and replace them with new elements such as replaceable cartridge configurations. Alternatively, if the chemical heating element does not last the duration required to complete the printing of the object, the operator may process the dispensing apparatus 370 described above and connect it to a new dispensing apparatus.

Both the structural and biological materials dispensed by the dispensing apparatus described above may require some sort of pre-treatment prior to dispensing. Examples of pre-processing may include, but are not limited to, mixing, selecting, changing the concentration of materials. Fig. 5 shows an example of a dispensing element comprising different mechanisms for the pre-treatment of the material to be dispensed. Any of the dispensing apparatus described with reference to the above figures may include one or more of these dispensing elements.

View 'a' is a side view of a single-use biomaterial dispensing element 500 that includes a mixing device that includes a shaft with one or more impellers 502 that may be connected to an external magnetic or gear shaft connection 504 that includes a seal. The shaft coupling may be a structure that drives the rotation of the shaft and impeller 502.

The inner tube for the biological material may include a plurality of baffles 506 to help mix and distribute the biological material cleanly received from the feed source 508. The mixing apparatus and baffle 506 may allow for proper mixing and homogenization of the heterogeneous material for easy dispensing of viscous materials, and/or for facilitating dispensing of denser or less dense materials such as cells while simultaneously removing cell debris when dispensing cells. Additionally or alternatively, a sparger (not shown) and/or micro-sparger (not shown) with a sterile air connection (not shown) may be used to properly aerate and mix the biological material prior to dispensing. Additionally, the biomaterial may be combined with a gelling agent, hydrogel, alginate, or thickening agent to aid in precise dispensing and attachment to the structure and/or scaffold. The thickener may be added within the inner tube of the single-use second dispensing element 500 through an upstream connection of feed material or via a spare sterile connector (not shown). Thickeners may require vigorous mixing with mixing equipment to achieve proper stability for dispensing.

View 'B' is a side view of the single-use second dispensing element 510 including one or more inner roller elements 512, the one or more inner roller elements 512 being connectable to an external drive mechanism and/or a drive mechanism of a connected multiple-use structural material dispensing element by a magnetic or gear connection 516. A drive mechanism (not shown) may drive the inner roller elements 512 using gear shafts, magnetic assemblies, pneumatic air sources, and/or hydraulic fluid sources. The inner roller element 512 can facilitate mixing and dispensing of the biological material that is cleanly received from the feed source 514. The roller elements may include a plurality of projections or impeller blades of different pitches and lengths to assist in moving or selecting materials of defined gauge prior to dispensing. In addition, the interior roller elements 512 can facilitate the distribution of specific materials, such as cells, having certain defined shapes and densities.

View 'C' is a side view of the single-use second dispensing element 520, the single-use second dispensing element 520 including one or more internal membrane elements 522 for concentrating or diluting biological material prior to dispensing. The inner thin film element 522 may be incorporated into the inner tube and used to remove fluid material from the biological material prior to dispensing using the external connection 524 and the vacuum force 526. The inner thin film element 522 may be sized to appropriately remove selected materials and control the removal force to protect remaining biological material, such as for removing fluids for concentration while maintaining healthy cells for dispensing. In other examples, the sterile fluid may be injected through the sterilization grade membrane element to the second dispensing element 520 to dilute the biological material cleanly received from the feed source 528 to a particular concentration. Examples are for reducing the trypsin concentration used to remove cells from the attachment plate, or providing chemical assistance to promote adhesion of cells or biological material to the printed structural material. The biomaterial dispensing tip portion 530 may include a luer lock connection or other attachment mechanism to attach to a size filter device, which size filter device 532 may be placed just prior to dispensing the biomaterial. The size filter device 532 may provide a sterile grade fluid, thus removing any potential bacterial contamination while allowing small biological materials such as proteins to pass through. The plurality of inner membrane elements 522 and the size filter device 532 may be fully testable.

View 'D' is a side view of the single-use second dispensing element 540, the single-use second dispensing element 540 including a single-use cell concentrator device 542 for controlling cell retention and concentration prior to dispensing, the single-use cell concentrator device 542 such as

The single-use cell concentrator device 542 can be cleanly connected to a biomaterial feed source 544 having two lines. By sedimentation in the centrifugal force field, the material is concentrated by means of a flow of material within the interior of the cell concentrator device 542, similar to centrifugation but without movable parts. The cells are concentrated and enter the inner tube via a concentration underflow connector 546 of the single-use biomaterial dispenser 540, while the cell debris and used media are removed via overflow connector 548. In other examples, the opposite product may be desired, and the single-use concentrator device 542 connection may be changed to supply single-use biomaterial dispenser 540 using line 548, while material is discarded from concentrate underflow connection 546. In other words, the cells may be discarded and the used media including the desired biomaterial may be harvested and used within the inner tube of the single-use biomaterial dispenser 540.

The handheld dispensing apparatus may be connected to the source of biological material via a sterile connection assembly, which may include, but is not limited to, any combination of a filtration system, a buffer vessel container, a tubular, a fermentor, a lateral flow assembly, a membrane adsorber, a centrifuge device, and an incubator.

Fig. 6 shows an example of a system 600 including a handheld dispensing device 624 and a source of biological material 602. The handheld dispensing device 624 may include one or more of the features of the dispensing devices described with reference to fig. 1-5.

The sterile printing and feeding material system 600 may include a source of biological material 602, such as a single-use bioreactor, which may be, for example, a microbial reactor, which is connected to a filtration system via a sterile connector 604. The filtration system (or filter system) may include one or more filters including, but not limited to, a depth filter 606, a pre-filter 608, and a sterilization grade filter 610. The filter system is optional if the cells and/or cell products that will be captured within the filter are the desired bio-feed material for printing.

The filter system may be connected to the buffer vessel container 614, illustratively by an additional sterile connector (not shown), or may be sterilized as a complete assembly. The buffer vessel container 614 may be filled with material filtered from the bioreactor 602, which may be driven by a constant pressure or constant flow source. The sterilization level vent filter 616 may allow the buffer vessel container 614 to vent during filling. After the filtration process is completed or the buffer vessel container 614 is full, the valve 612 to the filter system may be closed and a regulated compressed air line 618 may be attached to the sterilization grade air filter 616.

The pressure drives the liquid up the dip tube 620 and into the tube, which is connected to a dispensing apparatus 624 via a sterile connector 622. The material from the buffer vessel container 614 may be concentrated using cell retention and concentration equipment such as a gamma radiation hydrocyclone (not shown). In addition, the biomaterial may be attached to a sensor device and/or have an integrated sensor device for cell counting and cell viability. Sensor devices for cell counting and cell viability may include, but are not limited to, nuclear counters, flow cytometers and/or radio frequency impedance devices, preferably

A ViaMass sensor unit.

An operator may utilize the distribution device 624 with sufficient airflow in a clean environment, such as a laminar flow hood or bio-safety cabinet, or in a sterile environment, such as an isolator, glove box, or sterile room, to prevent contamination. An operator may use the structural material dispensing elements of dispensing apparatus 624 to precisely control the dispensing of structural material onto containers such as perforated plates 626 or printing trays to form scaffolds or structures supporting biological material. The processed biomaterial may be precisely deposited onto the structural material within the porous plate 626 using the biomaterial dispensing element of the dispensing apparatus 624. The 3D printed object within the porous plate 626 is formed by layer-by-layer additive printing of the build material from the manually-manipulated dispensing apparatus 624. After printing the structural material, biological material may be added, and the printed objects within perforated plate 626 may be filled with a nutrient fluid medium. Perforated plates 626 may be covered, removed from the printing environment, and incubated within the incubation container for further study, sampling, and/or evaluation.

Fig. 7 shows an example of a system 630 that includes a handheld dispensing apparatus 680 and multiple sources of biological material, such as a single-use bioreactor 632 and a single-use bioreactor 654. Handheld dispensing device 680 may include one or more of the features of the dispensing devices described with reference to fig. 1-5.

Sterile printing and feeding material system 630 may include at least single-use bioreactor 632 and single-use bioreactor 654, with single-use bioreactor 632 and single-use bioreactor 654 connected to their respective filter assemblies via

aseptic connectors

634 and 656. The filtration system for the first single-use bioreactor 632 may include one or more filters including, but not limited to, a depth filter 636, a pre-filter 608, and a sterilization grade filter 640. The filtration system for the second single-use bioreactor 654 may include one or more filters including, but not limited to, a pre-filter 658, a mycoplasma retentive filter 660, and a virus retentive filter 662. The filter system components are optional if the cells and/or cell products that will be captured within the filter are the desired bio-feed material for printing.

The filter system assembly may be connected to the buffer vessel container 644 and the buffer vessel container 666, illustratively by means of further aseptic connectors (not shown) or may be sterilized as a complete assembly. Buffer vessel container 644 and buffer vessel container 666 can be filled with materials processed from single-use bioreactor 632 and single-use bioreactor 654, which can be driven by a constant pressure or constant flow source. The sterilization level vent filter 646 and the sterilization level vent filter 668 may allow the buffer vessel container 644 and the buffer vessel container 666 to be vented during filling. After the filtration process is completed or buffer vessel container 644 and buffer vessel container 666 are filled, valves 642 and 664 to the filter system components may be closed and adjusted compressed air line 648 and compressed air line 670 may be attached to sterilization grade air filter 646 and sterilization grade air filter 668, respectively.

The pressure drives the liquid up the dip tube 650 and the dip tube 672 and into the tubing, which is connected to the dispensing apparatus 680 via the sterile connector 652 and the sterile connector 674. A plurality of biomaterial feed sources may be cleanly connected to the manifold 676 on the distribution apparatus 680. A selection valve 678 is located on the manifold 676 and can be used to select the feed source connected to the inner tube of the single-use biomaterial dispensing element during dispensing.

An operator may use the structural material dispensing elements of the dispensing apparatus 680 to precisely control the dispensing of structural material onto containers such as perforated plates 682 or printing trays to form a rack or structure supporting biological material. The processed biological material may be precisely deposited onto the structural material within the porous plate 682 using the biological material dispensing components of the dispensing apparatus 680. The 3D printed object within perforated plate 682 is formed by layer-by-layer additive printing of structural material from a manually-operated dispensing apparatus 680. After printing the structural material, a biological material may be added, and the printed objects within perforated plate 682 may be filled with a nutrient fluid medium. Dispensing apparatus 680 can dispense material into at least one well within multi-well plate 682 from a single biological feed source, such as material originating from single-use bioreactor 632, or material originating from single-use bioreactor 632 and single-use bioreactor 654 can be dispensed within at least one well within multi-well plate 682. Different feed sources may be dispensed by an operator onto different portions of the structural material or scaffold to form a finished object. Perforated plates 682 may be covered, removed from the printing environment, and incubated within an incubation container for further study, sampling, and/or evaluation.

Fig. 8 shows an example of a system 700 that includes a handheld dispensing device 742, a source of biological material, such as a single-use bioreactor 702, a centrifuge assembly 706, and a lateral flow assembly 728. The handheld dispensing device 742 may include one or more of the features of the dispensing devices described with reference to fig. 1-5.

Sterile printing and feeding materials system 700 may include a single-use bioreactor 702 connected to a centrifuge assembly 706 via a sterile connector 704. The filtration system components may be connected to the centrifuge component 706 via sterile connectors (not shown) and include one or more filters including, but not limited to, a depth filter 708, a pre-filter 710, and a sterilization grade filter 712. The filter system is optional if the cells and/or cell products that will be captured within the filter are the desired bio-feed material for printing.

The filter system assembly may be connected to the buffer vessel container 716, illustratively by an additional sterile connector (not shown), or may be sterilized as a complete assembly. The buffer vessel container 716 is filled with material filtered from the bioreactor, which may be driven by a constant pressure or constant flow source. The sterilization grade vent filter 718 may allow the buffer vessel container 716 to vent during filling. After the filtration process is completed or the buffer vessel container 716 is full, the valve 714 of the filter system may be closed and a conditioning compressed air line 720 may be attached to the sterilization grade air filter 718.

The pressure drives the liquid up the dip tube member 722 and into the tube member, which is connected to the pre-sterilized membrane adsorber 726 via the sterile connector 722. The membrane adsorber 726 may be a set of delamination membrane-bearing functions for reversible binding of biomolecules. The desired molecules may be captured using a membrane adsorber and eluted later, or undesired molecules may be removed by membrane adsorption prior to further processing. The membrane adsorber 726 may be connected to a pre-sterilization lateral flow assembly 728. The lateral flow assembly 728 may include a plurality of microfiltration and/or ultrafiltration cartridges of varying sizes.

Lateral flow assembly 728 may be connected to buffer vessel container 732 via an aseptic connector (not shown). The surge vessel receptacle 732 is filled with filtered and/or concentrated material from the lateral flow assembly 728, which may be driven by a constant pressure or constant flow source. Additionally or alternatively, common bioprocess processing methods of other biological materials may occur, such as column chromatography, High Performance Liquid Chromatography (HPLC), Fast Protein Liquid Chromatography (FPLC), and one of these other processes may fill buffer vessel container 732. The sterilization grade vent filter 734 may allow the buffer vessel container 732 to be vented during filling. After the lateral flow process is completed or buffer vessel container 732 is filled, valve 730 to the lateral flow assembly may be closed and a regulated compressed air line 736 may be attached to sterilization grade air lateral flow actuator 734.

The pressure drives the liquid up to the dip tube 738 and into the tube, which is connected to the dispensing apparatus 742 via the sterile connector 740. An operator may use the structural material dispensing elements of dispensing apparatus 742 to precisely control the dispensing of structural material onto containers such as perforated plates 744 or printing trays to form a scaffold or structure supporting biological material. The processed biomaterial may be precisely deposited onto the structural material within the porous plate 744 using the biomaterial dispensing element of the dispensing apparatus 742. The 3D printed object within the perforated plate 744 is formed by layer-by-layer additive printing of structural material from a manually-operated dispensing apparatus 742. After printing of the structural material, biological material may be added, and the printed objects within the porous plate 744 may be filled with a nutrient fluid medium. The perforated plate 744 may be covered, removed from the printing environment, and incubated within an incubation container for further study, sampling, and/or evaluation. Additionally or alternatively, the operator may dispense the biological material onto a backup substrate such as a membrane (not shown) and/or a diagnostic tape (not shown). Dispensing apparatus 742 may spray precipitated proteins and/or other concentrated ultrafilter material onto the membrane strip for use in diagnostic analysis. In addition, other structural components may be added to the thin film tape portion by additive printing of material from the dispensing apparatus 742 layer by layer.

As described with reference to fig. 1 and 2, the dispensing apparatus may include a positioning sensor. In general, the positioning sensor may be formed within, connected to, or inserted within the dispensing apparatus for tracking orientation and motion in three-dimensional space. In addition, the dispensing apparatus may include other internal sensors to gather additional information about the dispensing process, such as the dispensed volume or the dispensing speed. Alternatively, data related to the dispensing process of the dispensing apparatus, such as location, orientation, motion, dispensed material, dispensed volume, and status, may be tracked within the workspace using an external monitoring device. Data generated by the internal sensors and/or the external monitoring device may be stored as files in an internal memory storage device, an external memory storage device, a connection memory storage device, and/or a network memory storage device. The stored data can be edited, for example, for scale-up, and used to print multiple copies of a 3D object in a large scale 3D printer of such single-use biometric 3D printers.

Fig. 9 shows an example of external monitoring settings for monitoring the handheld dispensing device 1010. The handheld dispensing device 1010 may include one or more of the features of the dispensing device described with reference to the above-described figures.

Fig. 9 shows a front view of an external monitoring system setup 1000 comprising an augmented reality system 1006, the augmented reality system 1006 comprising a camera and light array sensing device 1002 connected to a display device 1004 using a wired/wireless connection. The camera and light array sensing device 1002 may include one or more cameras, such as a video camera, a depth camera, an infrared camera, a thermal camera, or light detection and ranging (LIDAR), and one or more adjustable lights that sufficiently illuminate the workspace for optimal tracking markers. The camera and light array sensing device 1002 may monitor and image a workspace 1008, which workspace 1008 may include one or more identifying markers.

The workspace 1008 may be located within a clean environment with sufficient airflow to prevent contamination, such as a laminar flow hood or bio-safety cabinet, or within a sterile environment such as an isolator, glove box, or sterile room. Additionally, the workspace 1008 may be located on a table or table of a non-sterile or non-clean environment for printing multiple three-dimensional objects following a defined protocol practice.

The one or more identification marks may identify objects within the field of view of the workspace and provide linking information related to the one or more identification marks, encoding the protocol identifier for loading a specific program of instructions from a database to be followed for printing the plurality of objects. The identifying marker may be, for example, a static or variable augmented reality marker. The augmented reality marker may be a physical tag or a virtual tag that provides unique identification information and positioning information. The variable augmented reality marker may have at least two states (e.g., the variable augmented reality marker displays two different images), and presentation of one of those states may be triggered by input from an operator or computer product input, for example, at programmed intervals. Coordinate

markers

1022, 1024 may provide an enhanced coordinate system 1026 in which objects between coordinate

markers

1022, 1024 and within the field of view of sensing device 1002 may be tracked based on the relative distance between coordinate

markers

1022, 1024, which may be considered an enhanced image on display device 1004 as described in U.S. patent 8,749,396B2, 8,749,396B2, which is incorporated herein by reference. Display device 1004 may be a monitor, screen, projection display, wearable display such as a head mounted display device (HMD), augmented reality display, virtual reality display, or mixed reality display device.

Operator 1012 may use dispensing apparatus 1010 to dispense structural and/or biological materials to a dispensing container or printer tray, which may be, for example, a multi-well plate 1020. The augmented reality system 1006 may accurately track the movement of the dispensing device 1010 within the workspace 1008 in three dimensions by using one or more light emitting diodes 1018 and a variable marker 1016, both located on the dispensing device 1010, wherein the one or more light emitting diodes 1018 may illustratively be infrared light emitting diodes, and wherein each infrared LED emits a different specific wavelength. The variable indicia 1016 on the dispensing device 1010 may change presentation to the augmented reality system 1006 depending on the material to be dispensed selected, the initiation of dispensing, the speed of dispensing, the status of dispensing, and the volume of material dispensed. Augmented reality system 1006 may present augmented displays 1028 of multiple 3D virtual objects 1032, showing the type of material, shape of material, and volume of material needed to be dispensed to each well of either multi-well plate 1020 or print tray according to a defined protocol.

The augmented reality system 1006 may record the motion of the light emitting diode 1018 and the variable marker 1016 position and presentation as a 3D wire frame graph, the 3D wire frame being a virtual line that tracks the movement of the marker in three-dimensional space over time, and compare the marker's motion to a reference graph within preprogrammed tolerances, as described in U.S. patent 8,982,156B2, U.S. patent 8,982,156B2, which is incorporated herein by reference. When the variable marker 1016 changes its presentation to the augmented reality system 1006, the change may be recorded on a wire frame map stored by the augmented reality system. The dispensing device 1010 may include one or more location sensors 1014, the one or more location sensors 1014 including, but not limited to, a motion sensor, an orientation sensor, a gyroscopic sensor, an environmental sensor, a camera, a depth sensor, a magnetometer, an accelerometer, a proximity sensor, a GPS device, an IMU, and an internal or external positioning sensor. Information from one or more orientation sensors and positioning sensors of the dispensing device assembly 1010 may be communicated to the augmented reality system 1006 via a wired or wireless connection to provide additional real-time positioning information for the augmented reality display 1004.

Additionally, the augmented reality system 1006 may provide overlaid video and/or animation 1030 of the dispensing device 1010 properly programmed and properly positioned to physically print the 3D virtual object 1032. The program may be executed on the display 1004 so that the operator may follow the overlaid video and/or animation 1030 to properly complete the appropriate program and sequence associated with the performance of the work task. The overlay video and/or animation 1030 may automatically accelerate or decelerate to mimic the speed and steps of the operator 1012 based on infrared LED marker tracking, variable marker tracking, position sensor tracking, or a combination of the above. Alternatively, the dispensing device 1010, augmented display 1028, and location tracking information for the 3D virtual object 1032 to be printed may be displayed on a virtual reality display device (not shown) or a mixed reality display device (not shown). The operator may be evaluated and rated by software that tracks the movement and presentation of the variable markers within the operator defined system for performing or following the appropriate technique for the predetermined task within error. If the operator meets a certain level of proficiency, the augmented reality system 1006 may determine that the operator is qualified to meet the requirements for performing the work task. The qualification may be an initial qualification for the operator or one of the pre-programmed periodic qualifications such as an annual retraining and assessment section.

The dispensing device shown in fig. 1 to 9 is a hand-held dispensing device. However, alternatively, such dispensing devices having the same characteristics may be controlled by a robot control means. According to one example, the robot control tool may be manually controlled by an operator through communication with an external control device operated by the operator. According to another example, the robot control tool may be controlled by an automatically operating external control device and run preprogrammed operations for printing. Fig. 10 and 11 show examples of dispensing systems comprising a sterilizable chamber, a dispensing device and an external control device.

The dispensing system 800 shown in FIG. 10 may include a sterilizable chamber 802, the sterilizable chamber 802 including at least one robotic arm assembly 804, a port 814, and a transfer port 810, wherein the port 814 couples an external control device 830 to the robotic arm assembly 804 and the transfer port 810 is for the chamber 802. The chamber 802 may be located within a clean environment with sufficient airflow to prevent contamination, such as a laminar flow hood or bio-safety cabinet, or within a sterile environment such as an isolator, glove box, or sterile room. In one example, the chamber 802 may be a pre-sterilization chamber that includes a robotic arm assembly 804, a dispensing apparatus 806, and a plurality of containers or printing trays, such as multi-well plates 808. The dispensing apparatus 806 may be a single-use assembly that is sterilized with the pre-sterilization chamber 802, or the single-use assembly may be separately sterilized using an alternative sterilization method from the sterile chamber and cleanly inserted using a sterile connection and insertion method (not shown).

Illustratively, robotic arm assembly 804 may utilize one or more actuators to control the positioning and movement of the dispensing apparatus. The robotic arm assembly 804, including the plurality of actuators, may be constructed of sterilizable (gamma radiation and/or autoclavable) plastic material and a rubberized seal. For example, robotic arm assembly 804 may be controlled by using actuators to turn a rotating base. The actuators may be driven by hydraulic, pneumatic, electric or magnetically controlled methods (not shown). In one example, the movement of the robotic arm assembly 804 may be controlled via an external control device, which may be a manual controller operated by an operator, external to the sterilization chamber 802.

External control device 830 may utilize one or more hydraulic and/or pneumatic lines 818 to move fluid through ports 814 to actuators located on robotic arm assembly 804 to control movement. Line 818 may be filled with a sterile fluid through a fill assembly 820, wherein the fluid may apply hydraulic and/or pneumatic pressure. For example, the pipeline may be filled with a sterile hydraulic fluid, such as sterile filtered water. The sterile filtered water may be passed into the robotic arm assembly 804 and the external control device 830 after sterilization and set for use by an operator. The lines of the internal robotic arm assembly 804 may be connected to the external filling assembly 820 and/or the external control device 830 using sterile connectors (not shown). The purified water may enter through line 824, through sterilization grade filter 826, and then into fill assembly 820, which fill assembly 820 may act as a manifold to completely fill each of the individual lines 818. The interior of the line 818 may be purged of air by a sterilization grade vent filter 828, the sterilization grade vent filter 828 allowing displaced air to vent to atmosphere as the displaced air is displaced into the assembly by the sterile filtered water. When the charging of the fluid line is complete, the valve 822 on the fill assembly 820 may close. In the event of a leak or pressure loss, additional sterile filtered water, other fluids, or in other examples air or gas may be added to the line 818 via the fill assembly 820.

An external control device 830 may be used to control the movement of the robotic arm assembly 804. The external control device 830 may be in the shape of the dispensing device 806 to simulate the motion and control of the device by the operator's hand 834. Alternatively, external control device 830 may be a minimized simulation of the shape of a stylus or other physical shape or design of dispensing device 806, which provides for motion and external control by an operator of robotic arm assembly 804 inside sterile room 802.

A plurality of hydraulic and/or pneumatic pistons may be arranged as a piston assembly 836 and filled with fluid, wherein the pistons may be pushed and/or pulled by an operator. Movement of one of the pistons 836 may alter the movement of a seal inside the piston and alter the displacement of fluid inside, resulting in movement of a corresponding piston 812 on the robotic arm assembly 804. Motion is imparted by the pressure of the fluid moving through the tubing line into aseptic chamber 802.

The body 832 of the external control device 830 may include all of the same buttons, switches, and displays as the dispensing device 806. The data cables 838 may communicate data generated from, for example, pressing a button or other input from the body 832 to the internal distribution device 806 via the respective internal data cables 816. The data cable 816 and the data cable 838 may provide data, power, and/or fluid communication to the internal distribution facility 806. Illustratively, instructions from the external control device may include, but are not limited to, dispensing of material using a dispense and retract button, and selecting dispensed material (such as structural or biological material) using a material selector switch. Conversely, the internal data cable 816 may communicate sensor information such as location and orientation and related information from the internal dispensing device 806 to a corresponding data cable 838 on the external control device body 832.

The internal distribution device 806 and/or the external control device 830 may include a plurality of location sensors including, but not limited to, motion sensors, orientation sensors, gyroscopic sensors, environmental sensors, cameras, depth sensors, magnetometers, accelerometers, proximity sensors, GPS devices, IMUs, and internal or external location sensors. Information from the orientation and positioning of the biological three-dimensional material dispensing apparatus assembly 806 used by the operator may be saved in a file that can be utilized to print out copies of structural and biological materials in exactly the same manner as manual printing with a large-scale single-use biological 3D printer (not shown).

The purpose of the robotic arm assembly 804 is to move, manipulate and dispense material from the dispensing apparatus 806 inside the sterilization chamber 802 while the operator is comfortably operating outside the sterilization chamber 802. In practice, the operations within the isolator or glove box typically imply heavy glove handling, so that the precise control of dispensing the material to the small print tray or perforated plate 808 may not be sufficiently mobile.

Transfer hatch 810 may be used to cleanly remove objects from sterilization chamber 802 and/or connect to additional sterilization chambers to form a more complex assembly. Additionally, the robotic arm assembly 804 may be used to move material from one sterilization chamber to another through an attached transfer hatch 810.

FIG. 11 illustrates a dispensing system 850 including a chamber 852, where the chamber 852 may include at least one robotic arm assembly 854, a port 865, and a transfer hatch 860, where the port 865 is connected to an external control device (or automatically operated external control device) 880 and the transfer hatch 860 is used with the chamber 852. The chamber 852 may be within a clean environment with sufficient airflow to prevent contamination, such as a laminar flow hood or bio-safety cabinet, or within a sterile environment such as an isolator, glove box, or sterile room. Illustratively, the chamber 852 may be a pre-sterilization chamber that includes a robotic arm assembly 854, a dispensing apparatus 856, and a plurality of containers or printing trays, such as multi-well plates 858. The dispensing device 856 may be a single-use assembly that is sterilized with the pre-sterilization chamber 852, or the single-use assembly may be separately sterilized using an alternative sterilization method from the sterile chamber and cleanly inserted using a sterile connection and insertion method (not shown).

In one example, the robotic arm assembly 854 can utilize a plurality of actuators to control the positioning and movement of the dispensing device 856. The robotic arm assembly 854, which includes a plurality of actuators, may be constructed of sterilizable (gamma radiation and/or autoclave) plastic material and a rubberized seal. Illustratively, robotic arm assembly 854 may be controlled by utilizing an actuator to turn a rotating base. The actuators may be driven by hydraulic, pneumatic, electric or magnetically controlled methods (not shown).

In one example, robotic arm assembly 854 may be controlled via an external control device 880. External control device 880 may utilize a plurality of hydraulic and/or pneumatic lines 866 to move pressurized fluid to actuator assemblies 862 on robotic arm assembly 854 to control movement. The line 866 may be filled with sterile fluid through the fill assembly 868, where the fluid may apply hydraulic and/or pneumatic pressure. For example, the pipeline may be filled with a sterile hydraulic fluid, such as sterile filtered water. Sterile filtered water may be passed into robotic arm assembly 854 and external control device 880 after sterilization and set up for use by an operator. The tubing of the internal robotic arm assembly 854 may be connected to the external filling assembly 868 and/or the external control device 880 using sterile connectors (not shown). Purified water may enter through the line 870, through the sterilization grade filter 872, and then into the fill assembly 868, which may act as a manifold to substantially fill each of the individual lines 866. The interior of the line 866 may be purged of air by the sterilization grade vent filter 874, the sterilization grade vent filter 874 allowing the displaced air to vent to atmosphere as the displaced air is displaced into the assembly by the sterile filtered water. When the charging of the fluid line is complete, the valve 876 on the fill assembly 868 may close.

An external control device 880 may be used to control the movement of the robotic arm assembly 854. A plurality of hydraulic and/or pneumatic pistons disposed in piston assembly 882 may be filled with fluid and the movement of a piston head (not shown) may be automatically controlled with a processing device 886. The memory storage device 888 may store a local program to the external control device 880 to control the movement of the robotic arm assembly 854 within the program for executing printed objects within the sterile chamber 852 using the robotic arm assembly 854 and the internal dispensing device 856. The processing device 886 may also process sensor data and alter the movement of the robotic arm assembly 854 based on programs stored in the memory storage device 888.

A data cable 864 from the dispensing device 856 can be connected to the external control device 880 through a data connection 884 to communicate data from pre-programmed button presses and settings at the external control device 880 and to transmit data to the internal dispensing device 856 through the data cable 864. A data cable 864 may provide data, power, and/or fluid communication from a data connection 884 on the external control device 880 to the internal distribution device 856. Examples of instructions from the external control device 880 include, but are not limited to, dispensing of materials and selection of dispensed materials. Conversely, an internal data cable 864 may convey sensor data such as positioning and orientation and related information from the internal distribution device 856 to a corresponding data connection 884 on the external control device 880.

Additionally, the external control device 880 may include a radio communication device 890 to input robotic arm assembly control protocols, wireless sensor information, by communicating with external networks and/or mobile devices. The external control device 880 may receive wireless data 902 from a wireless external control device 894 using a wireless communication device 890, the wireless external control device 894 being a manual controller operated by an operator 895 outside of the sterilization chamber 852. The wireless external control device 894 may use the positioning information to send instructions to the external control device 880 to control the movement of the robotic arm assembly 854 inside the sterilization chamber 852. The wireless external control device 894 may be in the shape of a dispensing device 856 to simulate the motion and control of the device by the operator's hand 895. Alternatively, the wireless external control device 894 may be a stylus shape or other minimized simulation of the actual shape or design of the dispensing device 856.

The wireless external control device 894 may include a processing device 896, a memory storage device 898, a power device (not shown), such as a powered wired source or battery driven source, and a communication device 900, the communication device 900 wirelessly communicating 902 data from the movement of the wireless external control device 894 to an external control device 880 or another computer device. The wireless external control device 894 may include a robotic arm assembly holder 892 that mimics a robotic arm assembly in a sterile room to provide the operator with the sensation of controlling the actual device.

The wireless external control device 894 may include all of the same buttons, switches and displays as the dispensing device 856. The instructions from the wireless external control device 894, including the use of the dispense and retract buttons to dispense material and the use of the material selector switch to select to dispense material, may be communicated 902 wirelessly to the external control device 880 or another computer device. Data from sensors in actuators on the robotic arm assembly support 892 may be communicated to the wireless external control device 894 for processing, memory storage, and external communication. Wireless data 902 from wireless external control device 894 can be printed in real time within sterile chamber 852 by movement of robotic arm assembly 854 and dispensed using internal dispensing device 856. Alternatively, the wireless data 902 from the wireless external control device 894 may be stored in the memory device 888 and the memory device 898 as object print files for later execution.

The internal distribution device 856 and/or the wireless external control device 894 may include a plurality of positioning sensors including, but not limited to, motion sensors, orientation sensors, gyroscopic sensors, environmental sensors, cameras, depth sensors, magnetometers, accelerometers, proximity sensors, GPS devices, IMUs, and internal or external positioning sensors. Information from the orientation and location of the dispensing device 856 or the wireless external control device 894 used by the operator may be saved in a file that can be utilized to print out copies of the structural and biological materials in exactly the same manner as manual printing with a large scale single use biological 3D printer 910. Additionally or alternatively, data communications 902 from a positioning sensor on the wireless external control device 894 may be used in real-time to practice printing virtual objects using the augmented reality display 904, the virtual reality display 906, and/or a mixed reality display (not shown). The operator may move the wireless external control device 894 and may virtually implement comparable motion and dispensing actions through the use of augmented reality, virtual reality, and/or mixed reality computer programs. This would allow an operator to practice the printing of multiple virtual objects before printing the actual object without wasting valuable structural and/or biological materials. Files for printing in an augmented reality, virtual reality, and/or mixed reality environment may be saved in memory storage and executed using the external control device 880 and/or a large-scale single-use biometric 3D printer 910.

The purpose of the robotic arm assembly 854 is to move, manipulate and dispense material from the dispensing apparatus 856 inside the sterilization chamber 852 while an operator comfortably operates outside the sterilization chamber 852. Indeed, operation within an isolator or glove box typically means handling with heavy gloves, so that precise control of dispensing material to a small print tray or multi-well plate 858 may not be adequately maneuvered.

The transfer hatch 860 may be used to cleanly remove objects from the sterilization chamber 852 and/or connect to additional sterilization chambers to form a more complex assembly. Additionally, the robotic arm assembly may be used to move material from one sterilization chamber to another through an attached transfer hatch 860.

A large scale single use biological 3D printer 910 may operate within a sterile chamber 912 having a printing platform 918 and a printer head 926, where the printing platform 918 is driven by a hydraulic and/or pneumatic linear actuator and the printer head 926 has a hinged joint 922 and a hinged joint 924 as described in US patent application 14/927,848, US patent application 14/927,848 being incorporated herein by reference. At least two hinged

joints

922 and 924 on the printer head 926 allow the printer head dispenser 928 to be positioned at multiple angles with respect to the print tray 920. The hydraulically and/or pneumatically driven linear actuator 914 and the hydraulically and/or pneumatically driven linear actuator 916 extend at different heights, resulting in the print platform 918 and the print tray 920 being positioned at an angle relative to the printer head dispenser 928. The multi-axis positioning of the print tray 920 at multiple angles, and the multi-axis positioning of the printer head dispenser 928, allow additional degrees of freedom for printing using a printer set up with a standard 3-axis coordinate printing system and increased flexibility in printing. These additional degrees of freedom mimic the movements an operator would make during printing of objects using the dispensing device 856 device and/or the wireless external control device 894.

Claims

1. A hand-held dispensing device comprising:

a first dispensing element configured to dispense a structural material;

a second dispensing element configured to dispense biological material;

at least one temperature regulating element in at least one of the first and second dispensing elements, the at least one temperature regulating element configured to regulate a temperature of at least one of the structural material and the biological material to be dispensed; and

a thermal protection barrier located between the first distribution element and the second distribution element,

wherein the second dispensing element is single-use and sterilizable, an

Wherein the first distribution element is connectable to the second distribution element to allow electrical power, data and/or fluid communication between the first and second distribution elements.

2. The handheld dispensing apparatus of claim 1, wherein the first dispensing element is releasably connected to the second dispensing element via an attachment mechanism.

3. A hand-held dispensing device as claimed in claim 1 or 2, wherein the entire hand-held dispensing device is single-use and sterilisable.

4. The handheld dispensing device of claim 1 or 2, further comprising a plurality of dispensing elements configured to dispense material related to the biological material, wherein the plurality of dispensing elements are connectable to at least one of the first dispensing element and the second dispensing element.

5. The handheld dispensing device of claim 1 or 2, further comprising a material selector switch configured to select the structural material or the biological material for dispensing by the handheld dispensing device.

6. The handheld dispensing device of claim 1 or 2, further comprising at least one modification tool configured to modify at least one of the dispensed structural material and the dispensed biological material.

7. The hand-held dispensing device of claim 1 or 2, further comprising:

at least one line configured to convey a temperature regulating fluid;

at least one temperature regulating element comprising an assembly to circulate the temperature regulating fluid and configured to regulate a temperature of at least one of the structural material and the biological material to be dispensed.

8. The hand-held dispensing device of claim 1 or 2, further comprising:

a single-use chemical temperature conditioning element configured to use a chemical reaction for single-use temperature conditioning of at least one of the structural material and the biological material to be dispensed.

9. The hand-held dispensing device of claim 1 or 2, wherein at least one of the first dispensing element, the second dispensing element, and plurality of dispensing elements comprises at least one of a hydraulic, pneumatic, magnetic, electrical, and manual drive mechanism configured to control movement of material until the material is dispensed from the dispensing tip.

10. The handheld dispensing device of claim 1 or 2, further comprising a positioning sensor configured to track orientation and movement of the handheld dispensing device in three-dimensional space.

11. A hand-held dispensing device as claimed in claim 1 or 2, further comprising at least one of a light emitting diode and an identification tag, the at least one of the light emitting diode and the identification tag being configured to be monitored by an external monitoring arrangement.

12. A system, comprising:

the handheld dispensing device of any one of claims 1 to 11;

at least one source of biological material; and

at least one aseptic connection assembly configured to connect the at least one source of biological material to the handheld dispensing apparatus.

13. The system of claim 12, wherein the at least one biomaterial source comprises a plurality of biomaterial sources, the at least one sterile connection assembly comprises a plurality of sterile connection assemblies, and the handheld dispensing apparatus comprises a manifold configured to select the biomaterial source to be connected to the second dispensing element during dispensing.

14. A system, comprising:

the hand-held dispensing device of claim 11;

a monitoring arrangement comprising at least one camera, wherein the monitoring arrangement is configured to monitor the handheld dispensing device by tracking the handheld dispensing device using the at least one of the light emitting diode and the identifying indicia.